Method of making a 3-halo-2-methylquinoline



dium hydroxide to obtain 3-hydroxy-2-methylquinoline, reduced with hydrogen in the presence of Raney nickel to obtain 3-hydroxy-2-methyl- 1,2,3,4-tetrahydroquinoline and this compound in turn reacted with glyceryl chlorohydrin, for example, to obtain N-,8,'y-dihydroxypropyl-B-hydroxy 2 methyl 1,2,3,4 tetrahydroquinoline which can be coupled with the diazonium form of p-nitroaniline, p-aminoacetophenone, ochloro-p-nitroaniline, o-cyano-p nitronaniline and similar aniline compounds to obtain dyes for cellulose acetate. 3-chloro-Z-methylquinoline can also be treated with sodium methylate to obtain 3-methoxy-2-methylquinoline which can be treated as 3-hydroxy-Z-methylquinoline to obtain N-B/y-dihydroxypropyl -3 methoxy 2- methyl-l,2,3,4-tetrahydroquinoline. Other 3- chloro-2-methylquinoline or 3-bromo-2-methylquinoline compounds can be used in place of 3- ohloro-2-methylquion1ine. Similarly the nitrogen atom of the resultin tetrahydroquinoline compounds can be substituted with another hydroxyalkyl group such as a fi-hydroxyethyl group or a B-hydroxypropyl or an alkyl group such as a methyl group or an ethyl group. The manner of introducing these groups is well known to those skilled in the art to which this invention is directed.

The following examples illustrate the process and the compounds of our invention.

Example 1 321 grams of m-toluidine, 480 cc. of hydrochloric acid (sp. gr. 1.18), 540'grams of arsenic acid and 180 cc. of water were heated to refluxing (114 C.) in a B-necked flask equipped with a reflux condenser, stirrer, and dropping funnel. At this point the heating was discontinued and the addition of 336 grams of a-ChlOI'O crotonaldehyde started. The rate of addition was so adjusted that the reaction mixture remained at gentle refluxing conditions. In about 40 to 45 minutes the addition of the a-ChlOIO crotonaldehyde was complete and the reaction mixture was heated at refluxing conditions for 5 to 6 hours longer. Following this the reaction mixture was diluted with several times its volume of water and filtered. The addition of a sodium hydroxide solution to the filtrate in excess of that required to neutralize the acid present precipitated a gummy product which repeatedly extracted with hot benzene. The benzene in the extract was removed by distillation under a reduced pressure of about 20 mm. of mercury and the residue remaining was distilled at a pressure of 1 mm. of mercury. A fraction weighing 143 grams and having a boilin range of 93 C.-115 C. was found to contain 57% of a. mixture of 3-chloro-2,7-dimethy1quinoline and 3- chloro-2,5-dimethylquinoline. Purification by fractional crystallization from ligroin gave white crystals of 3-chloro-2,7-dimethylquinoline melting at 96-975 C. The results of an analysis for nitrogen and chlorine are given herewith Found Theoretical Per cent Nitrogen 7. 19 7. 31 Chlorine 18. 37 18. 52

By distillation of the residue remaining from the crystallization operation under reduced pressure (5 mm., for example) to remove the ligroin an oily mixture consisting principally of 3- chloro-2,5-dimethylquinoline is obtained. An oil consisting essentially of 3-chloro-2,5-dimethylquinoline is obtained on distilling this oily mixture under reduced pressure.

Example 2 A mixture of 93 grams of aniline, 160 cc. of hydrochloric acid (sp. gr. 1.18), 180 grams of arsenic acid and 60 cc. of water were heated together in a suitable reaction vessel to refluxing. 131 grams of a-chloro-fi-hydroxybutyraldehyde was warmed (to facilitate addition) and gradually added to the reaction mixture under refluxing conditions, following which the reaction mixture was refluxed with stirring for 6 hours. The reaction mixture was then diluted with several times its volume of water and filtered. Then a sodium hydroxide solution was added to the filtrate in an amount slightly greater than that necessaryto neutralize the acid present and the product which precipitated was repeatedly extracted with hot benzene. The benzene in the extract was removed by distillation under a reduced pressure of about 20 mm. of mercury and the residue remaining was distilled at a pressure of 1 mm. of mercury. The fraction distilling at 83-99 C. was found to contain 64% of 3-chloro-2-methylquinoline. Pure 3-chloro-2-methylquinoline was separated from the mixture by fractional crystallization from petroleum ether. It melted at 68-69" C.

Example 3 137 grams of 1-amino-2-methoxy-5-methylbenzene, 160 cc. of hydrochloric acid (sp. gr. 1.18), 180 grams of arsenic acid and 60 cc. of water are heated to refluxing in a 3-necked flask equipped with a reflux condenser, stirrer and dropping funnel. The heating is then discontinued and 112 grams of a-ChlOIO crotonaldehyde added at a rate just suflicient to maintain refluxing conditions. After the addition of the e-chloro crotonaldehyde the reaction mixture is heated under refluxing conditions for 5 to 6 hours after which it is diluted with several times its volume of water and filtered. Sodium hydroxide solution is added to the filtrate in excess of that required to neutralize the acid present and the precipitate which forms is repeatedly extracted with hot benzene. The benzene in the extract is removed by distillation under a reduced pressure of about 20 mm. of mercury and the residue remaining is distilled at a pressure of 1 mm. of mercury. 3-chloro 8 1nethoxy-2,5 dimethylquinoline is obtained. It is obtained as white crystals upon purification by crystallization from ligroin.

150 grams of nitrobenzene or 240 grams of onitrobenzene sulfonic acid can be substituted for arsenic acid in the foregoing example. Similarly, 137 grams of A5205 can be used in place of arsenic acid. Where AS205 is used in place of arsenic acid somewhat more water is employed.

Example 4 446 grams of the nitrobenzene sulfonation mixture obtained when 304 grams of nitrobenzene are sulfonated with 1370 grams of 20% oleum, are diluted with grams of water and 107 grams of m-toluidine are added. The mixture is heated to C. and 164 grams of a-bromo crotonaldehyde is added while maintaining the temperature below C. The reaction mixture is then heated for an additional 56 hours after which it'is worked up in accordance with the ,talline; product. Ifract-ion consisting essentially 'ofi'3 -bromo 2', 5-di- 'meth'ylquinoline isalso obtained.

ncome-e procedure describeddmlflxamplel 1. 3-bromo-2,7- dimethylquinoline is obtained as a white, crys- Similarly, as in Examplefilya Following procedure idescribed herein .iore thecornpoundsindicatedhereinafter. can be prepared. For clarity the reactants 'fromwhich .they are prepared area-isoindicated. The...re-

-pound containing-nd substituents fiothercthanithe aminmgroupan'd the halogeniatomwith winem- -=ber sel ected iromzthegroup consisting: '0f-=.a=0h'10- mo '5 -:hydroxyn -butyraldehyde;anda 'chioro crotonaldehyde inithe: presenceiii-hydrochloric acid and an oxidizingagent.

3.-A procession-preparing a 3-chloro-2-methylq-uinoli-ne cornpourid which comprises reacting a compound selected from the group consisting of aniline, o-toluidine,*m-toluidine, p-toluidine, o- .-aanisidine, m-anisidine, p-anisidine, -.o1-nitroaniline, m-nitroaniline, p-nitroaniline, Z-methoxy- 3-chloro-2,6-dimethy1quinoline Product 'ZFReaetants p-toluidine'and a-chlorocrotonald'ehye.

itolullllnafind a-bromoicrotonaldehydc.

anisidine and a-chloro crotonaldehyde.

aniline and a-blOlllO crotonaldehyde. o-ethylaniline and a-chloro crotonaldehydc. m-(n-butyD-amlme and wchloro crotonaldchyde. o-(n-butoxy)-aniline and a-chloro crotonaldehyde. p-chloroaniline and a-chloro crotonaldehyde. o-bromoaniline and a-chloro crotonaldehyde. p-flucroani line and a-chloro crotonaldehyde. m-iodoaniline and a-chloro crotonaldchylle. p-aminoacetophenone and a-chloro crotonaldehyde. o-(n-butyryD-aniline and a-bromo crotonaldehyde. p-aminophenol and a-bromo crotonaldehyde. m-aminobenzoic acid and a-chloro crotonaldehyde.

l-amino-2-methoxy-5-methyl benzene and a-bromo crotonaldehyde.

o-trifluorou1ethylaniline and a-chloro crotonaldehyde. o-thiomcthylaniline and a-chloro crotonaldehyde. m-nitroaniline and a-chloro crotonaldehyde. o-nitroaniline and cz-blOlIlO crotonaldehyde. 2-amino-4-nitrophenol and a-chloro crotonaldehyde. o-cyanoaniline and a-chloro crotonaldehyde. Z-amino-l,4-dimethylbenzene and a-bI'OlJJO crotonaldehyde. o-sulfanilic acid and a-ciiloro crotonaldehyde. m-sulfanilic acid and a-chloro crotonaldehyde. p-sulfanilic acid and a-bromo crotonaldehyde. p-(n-butyryD-aminoaniline and a-bromo crotonaldehyde. m-acetaminoaniline and a-chloro crotonaldehyde.

While the process of our invention has been illustrated more particularly in connection with the use of hydrochloric acid as the mineral acid, it is to be noted that other mineral acids such as hydrobromic acid, hydrofluoric acid, ortho phosphoric acid and sulfuric acid, for example, can be used. Similarly, an oxidizing agent, such as nitrooenzene and o-nitrobenzene sulfonic acid, for

5-methylaniline and a mono halogen aniline compound containing no substituents other than the amino group and the halogen atom with a member selected from the group consisting of u.- chloro-p-hydroXy-n-butyraldehyde and a-OhlOlO crotonaldehyde in the presence of hydrochloric acid and arsenic acid.

4. A process for preparing a 3-bromo-2-methexample, can be used instead of arsenic acid or ylquinoline compound which comprises reacting its anhydride AS205. The a-chloro crotonaldea compound selected from the group consisting of hyde and a-bromo crotonaldehyde referred to in aniline, o-toluidine, m-toluidine, p-toluidine, othe foregoing tabulation can, of course, be reanisidine, m-anisidine, p-anisidine, o-nitroaniplaced by a-chloro-fi-hydroxy-n-butyraldehyde line, m-nitroaniline, p-nitroaniline, 2-methoxyand a bromo fi hydroxy-n-butyraldehyde, re- 5-methylaniline and a mono halogen aniline comspectively. pound containing no substituents other than the We claim: amino group and the halogen atom with a mem- 1. A process for preparing a compound selected ber selected from the group consisting of a afrom the group consisting of 3-chloro-2-methy1- bromo-fi-hydroxy-n-butyraldehyde and a-bromo quinoline compounds and 3 bromo 2 methylcrotonaldehyde in the presence of hydrochloric quinoline compounds which comprises reacting a acid and an oxidizing agent. compound selected from the group consisting of 5. A process for preparing a 3-bromo-2-methaniline, o-toluidine, m-toluidine, p-toluidine, oylquinoline compound which comprises reacting anisidine, rn-anisidine, p-anisidine, o-nitroania compound selected from the group consisting of line, m-nitroaniline, p-nitroaniline, 2-methoxyaniline, o-toluidine, m-toluidine, p-toluidine, o- 5-methylani1ine and a mono halogen aniline comanisidine, m-anisidine, p-anisidine, o-nitroanipound containing no substituents other than the line, m-nitroaniline, p-nitroaniline, Z-methoxyamino group and the halogen atom with a com- S-methylaniline and a mono halogen aniline compound selected from the group consisting of apound containing no substituents other than the chloro crotonaldehyde a. chloro B hydroxy-namino group and the halogen atom with a membutyraldehyde, a-bromo-;8-hydroXy-n-butyraldeher selected from the group consisting of ahyde and a-bIOIIlO crotonaldehyde in the presence brommc-hydroxy-n-butyraldehyde and a-bromo of a mineral acid and an oxidizing agent. crotonaldehyde in the presence of hydrochloric 2. A process for preparing a S-chloro-Z-methacid and arsenic acid. ylquinoline compound which comprises reacting 6. A process for preparing 3-chloro-2-methyla compound selected from the group consisting of quinoline which comprises reacting aniline with aniline, o-toluidine, m-toluidine, p-toluidine, oa member selected from the group consisting of anisidine, m-anisidine, p-anisidine, o-nitroanla-chloro-B-hydroxy-n-loutyraldehyde and a-ChlO- line, m-nitroaniline, p-nitroaniline, 2methoxyr0 crotonaldehyde in the presence of a mineral fi-methylaniline and a mono halogen aniline comacid and an oxidizing agent.

7 '7. A process for preparin 3-chloro-2-methy1- quinoline which comprises reacting aniline with a member selected from the group consisting of a-chloro-,B-hydroxy-n-butyraldehyde and a-ChlO- r crotonaldehyde in the presence of hydrochloric acid and arsenic acid.

JOSEPH B. DICKEY.

FRED C. DUENNEBIER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,752,492 Kyrides Apr. 1, 1930 1,806,564 Prill et a1 May 19, 1931 2,035,751 Kunz et a1 Mar. 31, 1936 FOREIGN PATENTS Number Country Date 559,329 Germany Feb. 20, 1933 388,087 Great Britain Feb. 23, 1933 OTHER REFERENCES Busch et 9.1.: Beriohte, vol. 24, pp. 3692-3694 (1891) Hollins: The Synthesis of Nitrogen Ring Compounds (Van Nostrand, New York, 1924), p. 266.

Braun et a1.: Berichte, 63-B, p. 3194 (1930).

Braun: Berichte, -B, p. 981 (1937).

Utermohlen: J. Org. Chem., v01. 8, pp. 544-548 (1943).

Fieser et al.: Organic Chemistry Health, Boston, 1944), pp. 214 and 215.

Certificate of Correction May 9, 1950 Patent No. 2,507,146

JOSEPH B. DIGKEY ET AL.

It is hereby certified that errors appear in the printed specification numbered patent requiring correction as follows:

Column 3, line 20, for methylquionline read methylguinoline; line 51, after the word whic insert was; columns 5 and 6, 1n the tabulation, second column thereof, last two lines, for

"p-(n-butyryD-eminoaniline and a-bromo crotonaldehyde.

m-ecetaminoaniline and a-chloro crotoneldehyde.

of the above read a-chloro crotonaldehyde.

m-acetam'inoan'iline and p-(n-butyryl)-a,mtno(milme and a-bromo crotonaldehyde.

and that the said Letters Patent should be read with these corrections therein that the record of the case in the Patent Ofiice.

the same may conform to d sealed this 15th day of August, A. D. 1950.

Signed an THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. A PERSON FOR PREPARING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-CHLORO-2-METHYLQUINOLINE COMPOUNDS AND 3-BROMO-2-METHLYQUINOLINE COMPOUNDS WHICH COMPRISES REACTING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ANILINE, O-TOLUIDINE, M-TOLUIDINE, P-TOLUIDINE, OANISIDINE, M-ANISIDINE, P-ANISIDINE, O-NITROANILINE, M-NITROANILINE, P-NITROANILINE, 2-METHOXY5-METHYLANILINE AND A MONO HALOGEN ANILINE COMPOUND CONTAINING NO SUBSTITUENTS OTHER THAN THE AMINO GROUP AND THE HALOGEN ATOM WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ACHLORO CROTONALDEHYDE A-CHLORO-B-HYDROXY-NBUTYRALDEHYDE, A-BROMO-B-HYDROXYN-BUTYRALDEHYDE AND A-BROMO CROTONALDEHYDE IN THE PRESENCE OF A MINERAL ACID AND AN OXIDIZING AGENT. 